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    Summary
    EudraCT Number:2012-005159-18
    Sponsor's Protocol Code Number:CRO2047
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-08-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2012-005159-18
    A.3Full title of the trial
    An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    LeoPARDS - An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis.
    A.3.2Name or abbreviated title of the trial where available
    LeoPARDS
    A.4.1Sponsor's protocol code numberCRO2047
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorImperial College, London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNIHR Efficacy and Mechanism Evaluation (EME) Programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImperial College London
    B.5.2Functional name of contact pointAnthony Gordon
    B.5.3 Address:
    B.5.3.1Street AddressICU 11N, Charing Cross Hospital
    B.5.3.2Town/ cityFulham Palace Road
    B.5.3.3Post codeW6 8RF
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number020 3313 0657
    B.5.5Fax number020 3311 1975
    B.5.6E-mailanthony.gordon@imperial.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Simdax
    D.2.1.1.2Name of the Marketing Authorisation holderOrion Corporation
    D.2.1.2Country which granted the Marketing AuthorisationFinland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLevosimendan
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLevosimendan
    D.3.9.1CAS number CAS-141505-3
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Septic shock.
    E.1.1.1Medical condition in easily understood language
    Low blood pressure due to severe infection
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10028237
    E.1.2Term Multiple organ failure
    E.1.2System Organ Class 100000004867
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10040070
    E.1.2Term Septic shock
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objectives of this trial are:

    1. To ascertain if levosimendan reduces the incidence and severity of organ failure as compared to placebo in adult patients who have septic shock.
    2. To identify the effect of levosimendan on the function of individual organs function in septic shock.
    3. To establish the safety profile and the metabolism of levosimendan by the body in this group of patients.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this trial are:

    1. To identify whether levosimendan reduces the need for and duration of blood pressure support with conventional adrenaline-like drugs called catecholamines and whether levosimendan reduces the damage to the heart that is associated with septic shock and the use of these drugs.
    2. To establish whether levosimendan affects the degree of inflammation that is seen in septic shock by measuring the levels of chemicals that are released in response to overwhelming infection.
    3. To collect longer-term (3 and 6 month) outcome data to help inform the appropriate outcome measure for a subsequent larger trial if the efficacy of levosimendan is confirmed in this study.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The target population is adult patients (≥18 years) who require vasopressor support for the management of sepsis despite fluid resuscitation. Inclusion criteria will use the internationally-established consensus definitions of sepsis. In brief:

    Fulfil 2/4 of the criteria of the systemic inflammatory response syndrome (SIRS) due to known or suspected infection within the previous 24 hours. The SIRS criteria are:
    (1) fever (>38 C) or hypothermia (< 36 C),
    (2) tachycardia (heart rate > 90 beats per minute),
    (3) tachypnoea (respiratory rate > 20 breaths per minute or PaCO2 < 4.3 kPa) or need for mechanical ventilation,
    (4) abnormal leukocyte count (> 12,000 cells/mm3, < 4000 cells/mm3, or > 10% immature [band] forms).

    Hypotension, despite adequate intravenous fluid resuscitation, requiring treatment with a vasopressor infusion (e.g. noradrenaline / adrenaline / vasopressin analogue) for at least four hours and still having an ongoing vasopressor requirement at the time of randomisation.
    E.4Principal exclusion criteria
    The exclusion criteria are as follows:

    1. More than 24 hours since meeting all the inclusion criteria
    2. End-stage renal failure at presentation (previously dialysis-dependent).
    3. Severe hepatic impairment (Child-Pugh class C).
    4. A history of Torsades de Pointes.
    5. Significant mechanical obstructions affecting ventricular filling or outflow or both.
    6. Treatment limitation decision in place (e.g. DNAR or not for ventilation/ dialysis).
    7. Known or estimated weight >135kg.
    8. Known to be pregnant.
    9. Previous treatment with levosimendan within 30 days.
    10. Known hypersensitivity to levosimendan or any of the excipients
    111.Known to have received another investigational medicinal product within 30 days or currently in another interventional trial that might interact with the study drug.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome will compare mean Sequential Organ Failure Assessment (SOFA) score after randomisation between treatment groups. This is a well validated scoring system assessing the severity of organ failures. The mean SOFA is predictive of mortality regardless of ICU length of stay and therefore no imputation for death is required. All SOFA scores while alive in ICU (excluding neurological component) will be used for all patients to calculate the mean SOFA score for each patient.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of ICU stay.
    E.5.2Secondary end point(s)
    CARDIOVASCULAR - Central venous oxygen saturations and cardiac output

    RENAL - Stage of Acute Kidney Injury

    RESPIRATORY - Time to extubation

    OTHER CLINICAL OUTCOMES
    28-day, hospital and three & six-month survival
    ICU and hospital length of stay, and ICU-free days
    Duration of renal replacement therapy
    Days free from catecholamine therapy

    Blood and urinary biomarkers

    PHARMACOKINETICS
    E.5.2.1Timepoint(s) of evaluation of this end point
    CARDIOVASCULAR - Over the first 96 hours

    RENAL - at Day 14
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned26
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    This study will end when the specified number of patients have been recruited and all patients have completed 6 month follow-up and the database is locked..
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days29
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days29
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 276
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state516
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The intervention is confined to administration of the study drug for a period of 24h whilst on the intensive care unit. Once the study drug infusion has finished no further intervention, other than standard care, is required.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-08-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-06-21
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